Substituted 5-carboxyamide pyrazoles and [1,2,4]triazoles as antiviral agents

ABSTRACT

The present invention provides compounds of formula I wherein X, Y, R 1 -R 7  are as defined herein. Compositions containing these compounds, and methods for inhibiting HCV RNA-dependent RNA polymerase and treating hepatitis C and related disorders using these compounds and compositions are also provided.

This application claims benefit of priority from U.S. provisional patentapplication Ser. No. 60/623,173 filed Oct. 29, 2004.

FIELD OF THE INVENTION

This invention relates to the inhibition of hepatitis C virus (HCV)replication. In particular, the invention relates to substitutedpyrazole and [1,2,4]triazole compounds, compositions containing thesecompounds, and methods for inhibiting HCV RNA-dependent RNA polymeraseand treating hepatitis C and related disorders using these compounds andcompositions.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus in theFlaviviridae family. Its 9.6 kb genome encodes for approximately 10proteins, including the structural capsid and envelope proteins, as wellas the nonstructural proteins NS3 (protease and helicase) and NS5B(polymerase). The viral RNA-dependent RNA polymerase (RdRp) isresponsible both for generating the intermediate minus-strand RNAtemplate and for the synthesis of progeny positive-strand genomic RNA(Ishii et al., Hepatology, 1227 (1999)). RdRp is used only in thereplication of RNA viruses and has very strict template specificities.Thus, RNA-dependent RNA polymerase enzymes, including HCV RdRp, areideal targets for antiviral drugs.

HCV has been implicated as the major causative agent in non-A, non-Bhepatitis (NANBH), particularly in blood-associated NANBH (BB-NANBH)(see, International Patent Application Publication No. WO 89/04669 andEuropean Patent Application Publication No. EP 381 216). NANBH is to bedistinguished from other types of viral-induced liver disease, such ashepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus(HDV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well asfrom other forms of liver disease such as alcoholism and primary biliarcirrhosis.

HCV has been shown to be capable of establishing a persistent infectionand has been implicated in cirrhosis of the liver and in induction ofhepatocellular carcinoma. HCV is believed to have infected approximately3% of the worldwide population. The prognosis for patients sufferingfrom HCV infection is currently poor. HCV infection is more difficult totreat than other forms of hepatitis due to the lack of immunity orremission associated with HCV infection. Current data indicates a lessthan 50% survival rate at four years post cirrhosis diagnosis. Patientsdiagnosed with localized resectable hepatocellular carcinoma have afive-year survival rate of 10-30%, whereas those with localizedunresectable hepatocellular carcinoma have a five-year survival rate ofless than 1%.

Existing therapies for HCV are limited, and only a few inhibitors of HCVRNA-dependent RNA polymerase are known. There is thus a need to identifyadditional HCV RdRp inhibitors and to identify the structural featuresrequired for potent HCV RdRp inhibitory activity.

SUMMARY OF THE INVENTION

The present invention provides a novel class of inhibitors of HCVRNA-dependent RNA polymerase (RdRp), pharmaceutical compositionscomprising one or more of these inhibitors, and methods of treatment orprevention of HCV or amelioration of one or more of the symptoms ofhepatitis C using one or more such compounds or compositions. Thepresent invention discloses compounds having the general structure shownin formula I:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein:

X is C(R⁸) or N;

R⁸ is H, halo, CF₃, C₁-C₆ alkyl, halo(C₁-C₆)alkyl, —OH, —SH, C₁-C₆alkoxy, C₁-C₆ alkylthio, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

Y is C(O) or S(O)₂;

R¹ is —CO₂R⁹, —C(O)R⁹, —C(O)NR⁹R¹⁰, —NR⁹C(O)R¹⁰, —NR⁹SO₂R¹⁰,—NR⁹SO₂NR⁹R¹⁰, —C(O)N(R⁹)OR¹⁰, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰,—C(O)NR⁹SO₂R¹⁰, —C(O)NR⁹NR⁹R¹⁰, —CN, —NR⁹C(O)CF₃, —NR⁹SO₂CF₃,—CH═N—OR²¹, —C(O)NR⁹CN, —C(O)NR⁹(CR¹⁹R²⁰)₁₋₁₂R¹¹,—C(O)N((R¹⁹R²⁰)₁₋₁₂R¹¹)₂, —NR⁹C(O)NR⁹(CR¹⁹R²⁰)₁₋₁₂CO₂R⁹, H, —OH,hydroxy(C₁-C₆)alkyl, C₁-C₆ alkyl, unsubstituted tetrazolyl, tetrazolylsubstituted with one or more moieties which can be the same or differentand are independently selected from the group consisting of alkyl,cycloalkyl, halo and aryl, unsubstituted thienyl, thienyl substitutedwith one or more moieties which can be the same or different and areindependently selected from the group consisting of alkyl, cycloalkyl,halo and aryl;

R² is cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, orcycloalkylalkyl, wherein each member of R² is optionally substitutedwith 1-4 R¹² moieties;

R³ is H or C₁-C₆ alkyl;

R⁴ is H, C₁-C₆ alkyl or C₁-C₆ alkoxy;

R⁵ is H, C₁-C₆ alkyl or C₁-C₆ alkoxy;

R⁶ is cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, orcycloalkylalkyl, wherein each member of R² is optionally substitutedwith 1-4 R¹² moieties;

R⁷ is H or C₁-C₆ alkyl; or R⁶ and R⁷, when attached to the samenitrogen, are optionally taken together with the attached nitrogen toform a five to seven membered ring having 0-1 additional heteroatomselected from N, O or S (in addition to said attached nitrogen), whereinsaid five to seven membered ring is optionally substituted with 1-3 R¹⁸moieties;

each R⁹ is independently H, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl, wherein each member except H is optionally substitutedwith 1-4 R¹² moieties;

each R¹⁰ is independently H, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl, wherein each member except H is optionally substitutedwith 1-4 R¹² moieties; or R⁹ and R¹⁰ when attached to the same nitrogenare optionally taken together with the attached nitrogen to form a fiveto sixteen membered monocyclic, bicyclic or tricyclic ring having 0-2additional heteroatoms (in addition to said attached nitrogen) selectedfrom N, O or S, wherein said monocyclic, bicyclic or tricyclic ring isoptionally substituted with 1-3 R¹⁸ moieties;

R¹¹ is —NR¹³SO₂R¹⁴, —CO₂R¹³, —OR¹³, —C(O)NR¹³R¹⁴, —NR¹³R¹⁴ or—C(O)NR¹³(CR¹⁹R²⁰)₁₋₁₂CO₂R²¹;

each R¹² is independently halo, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, —CN, —CF₃, —OR¹³, —SR¹³, —C(O)R¹³, —C(S)R¹³, —C(O)OR¹³,—C(S)OR¹³, —OC(O)R¹³, —OC(S)R¹³, —C(O)NR¹³R¹⁴, —C(S)NR¹³R¹⁴,—C(O)NR¹³OR¹⁴, —C(S)NR¹³OR¹⁴, —C(O)NR¹³NR¹³R¹⁴, —C(S)NR¹³NR¹³R¹⁴,—C(S)NR¹³OR¹⁴, —C(O)SR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(S)R¹⁴,—NR¹³C(O)OR¹⁴, —NR¹³C(S)OR¹⁴, —OC(O)NR¹³R¹⁴, —OC(S)NR¹³R¹⁴,—NR¹³C(O)NR¹³R¹⁴, —NR¹³C(S)NR¹³R¹⁴, —NR¹³C(O)NR¹³OR¹⁴, —NR¹³C(S)NR¹³R¹⁴,—(CR¹⁹R²⁰)₁₋₆OR¹³, —(CR¹⁹R²⁰)₁₋₆SR¹³—SO₂R¹³, —S(O)₁₋₂NR¹³R¹⁴,—N(R¹³)SO₂R¹⁴, —N(R¹³)SO₂NR¹³R¹⁴, —S(O)₁₋₂NR¹³OR¹⁴, —OCF₃, —SCF₃,—C(═NR¹³)NR¹⁴, —C(O)NR¹³(CH₂)₁₋₁₀NR¹³R¹⁴, —C(O)NR¹³(CH₂)₁₋₁₀OR¹⁴,—C(S)NR¹³(CH₂)₁₋₁₀NR¹³R¹⁴, —C(S)NR¹³(CH₂)₁₋₁₀OR¹⁴, haloalkyl, ═O, ═S,NO₂, —C(O)C(O)R¹³, —C(O)CH₂C(O)R¹³, methylenedioxy, or ethylenedioxy,wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl isoptionally substituted with 1-4 R¹⁵ moieties;

each R¹³ is independently H, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl, wherein each member of R¹³ except H is optionallysubstituted with 1-4 R¹⁵ moieties;

each R¹⁴ is independently H, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl, wherein each member of R¹⁴ except H is optionallysubstituted with 1-4 R¹⁵ moieties; or R¹³ and R¹⁴, when attached to thesame nitrogen, are optionally taken together with the attached nitrogento form a five to seven membered ring having 0-1 additional heteroatomselected from N, O or S (in addition to said attached nitrogen), whereinsaid five to seven membered ring is optionally substituted with 1-3 R¹⁸moieties;

each R¹⁵ is independently halo, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, —CN, —CF₃, —OR¹⁶, —SR¹⁶, —C(O)R¹⁶, —C(S)R¹⁶, —C(O)OR¹⁶,—C(S)OR¹⁶, —OC(O)R¹⁶, —OC(S)R¹⁶, —C(O)NR¹⁶R¹⁷, —C(S)NR¹⁶R¹⁷,—C(O)NR¹⁶OR¹⁷, —C(S)NR¹⁶OR¹⁷, —C(O)NR¹⁶NR¹⁶R¹⁷, —C(S)NR¹⁶NR¹⁶R¹⁷,—C(S)NR¹⁶OR¹⁷, —C(O)SR¹⁶, —NR¹⁶R¹⁷, —NR¹⁶C(O)R¹⁷, —NR¹⁶C(S)R¹⁷,—NR¹⁶C(O)OR¹⁷, —NR¹⁶C(S)OR¹⁷, —OC(O)NR¹⁶R¹⁷, —OC(S)NR¹⁶R¹⁷,—NR¹⁶C(O)NR¹⁶R¹⁷, —NR¹⁶C(S)NR¹⁶R¹⁷, —NR¹⁶C(O)NR¹⁶OR¹⁷,—NR¹⁶C(S)NR¹⁶OR¹⁷, —(CR¹⁹R²⁰)₁₋₆OR¹⁶, —(CR¹⁹R²⁰)₁₋₆SR¹⁶, —SO₂R¹⁶,—S(O)₁₋₂NR¹⁶R¹⁷, —N(R¹⁶)SO₂R¹⁷, —S(O)₁₋₂NR¹⁶OR¹⁷, —OCF₃, —SCF₃,—C(═NR¹⁶)NR¹⁷, —C(O)NR¹⁶(CH₂)₁₋₁₀NR¹⁶R¹⁷, —C(O)NR¹⁶(CH₂)₁₋₁₀OR¹⁷,—C(S)NR¹⁶(CH₂)₁₋₁₀NR¹⁶R¹⁷, —C(S)NR¹⁶(CH₂)₁₋₁₀OR¹⁷, haloalkyl, ═O, ═S,NO₂, —C(O)C(O)R¹⁶, —C(O)CH₂C(O)R¹⁶, methylenedioxy, or ethylenedioxy,wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl isoptionally substituted with 1-3 R¹⁸ moieties;

each R¹⁶ is independently H, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl orheteroaralkyl, wherein each member of R¹⁶ is optionally substituted with1-3 R¹⁸;

each R¹⁷ is independently H, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl orheteroaralkyl, wherein each member of R¹⁶ is optionally substituted with1-3 R¹⁸; or R¹⁶ and R¹⁷, when attached to the same nitrogen, areoptionally taken together with the attached nitrogen to form a five toseven membered ring having 0-1 additional heteroatom selected from N, Oor S (in addition to said attached nitrogen), wherein said five to sevenmembered ring is optionally substituted with 1-3 R¹⁸ moieties;

each R¹⁸ is halo, ═O, ═S, NO₂, alkyl, —OR²¹, —CN, —NR²¹R²², —C(O)R²¹,—C(O)OR²¹, —C(O)NR²¹R²², —CF₃, —N(R²¹)C(O)R²²,—(CH₂)₁₋₄—O—(CH₂)₁₋₄-phenyl, phenyl, or benzyl, wherein said phenyl orbenzyl is optionally substituted with 1-3 R²³;

each R¹⁹ is independently H, C₁-C₆ alkyl, or C₁-C₆ alkoxy;

each R²⁰ is independently H, C₁-C₆ alkyl, or C₁-C₆ alkoxy;

each R²¹ is independently H or alkyl;

each R²² is independently H or alkyl; and

each R²³ is independently halo, —NO₂, alkyl, —OR²¹, —CN, —NR²¹R²²,—C(O)R²¹, —C(O)OR²¹, —C(O)NR²¹R²², —CF₃, or —N(R²¹)C(O)R²².

The compounds represented by formula I, alone or in combination with oneor more other suitable agents disclosed herein, as well aspharmaceutical compositions comprising the same, are useful for treatingor preventing HCV infection, HIV infection, AIDS (Acquired ImmuneDeficiency Syndrome), and related disorders.

DETAILED DESCRIPTION

The present invention discloses substituted pyrazole and [1,2,4]triazolecompounds which are represented by structural formula I or apharmaceutically acceptable salt, solvate or ester thereof, wherein thevarious moieties are described above.

In one embodiment, X is C(R⁸).

In one embodiment, X is C(R⁸) and R⁸ is H or NH₂.

In another embodiment, X is N.

In another embodiment, Y is C(O).

In another embodiment, R³ is H or CH₃ and R⁷ is H or CH₃.

In another embodiment, R² is cycloalkyl, aryl, or aralkyl, wherein saidcycloalkyl, aryl, or aralkyl is optionally substituted with 1-2 R¹²moieties. In another embodiment, R² is phenyl, cyclohexyl, benzyl oradamantanyl, wherein said phenyl, cyclohexyl, benzyl or adamantanyl isoptionally substituted with 1-2 R¹² moieties. In another embodiment,each R¹² is independently —OR¹³, alkyl, halo, or CF₃; and R¹³ is alkyl;cycloalkylalkyl; aralkyl; aryl optionally substituted with —NH₂; orheteroaralkyl optionally substituted with alkyl. In another embodiment,R¹³ is benzyl; cyclopentylmethyl; cyclohexylmethyl; cyclobutylmethyl;cyclopropylmethyl; C₁-C₆ alkyl; thienylmethyl; phenyl optionallysubstituted with —NH₂; or N-pyrazolylmethyl which is optionallysubstituted with 1-2 methyl groups.

In another embodiment, R⁶ is cycloalkyl, aryl, or heteroaryl, whereinsaid cycloalkyl, aryl, or heteroaryl is optionally substituted with 1-2R¹² moieties. In another embodiment, R⁶ is cyclohexyl, cyclopentyl,phenyl, or pyridyl, wherein said cyclohexyl, cyclopentyl, phenyl, orpyridyl is optionally substituted with 1-2 R¹² moieties. In anotherembodiment, each R¹² is independently —OR¹³, —NHR¹³, —SR¹³,methylenedioxy, or a six-membered heterocyclyl; R¹³ is alkyl,cycloalkylalkyl, aralkyl, or aryl wherein said aryl is optionallysubstituted with 1-2 R¹⁵; and R¹⁵ is halo or alkyl. In anotherembodiment, R¹³ is benzyl; cyclopentylmethyl; cyclobutylmethyl;cyclopropylmethyl; C₁-C₆ alkenyl; phenyl; or phenyl substituted withhalo and methyl.

In another embodiment, R¹ is —C(O)NR⁹R¹⁰, —NR⁹C(O)R¹⁰, —NR⁹SO₂R¹⁰,—NR⁹SO₂NR⁹R¹⁰, —C(O)N(R⁹)OR¹⁰, —NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰,—C(O)NR⁹SO₂R¹⁰, —C(O)NR⁹NR⁹R¹⁰, —CN, —NR⁹C(O)CF₃, —NR⁹SO₂CF₃,—CH═N—OR²¹, —C(O)NR⁹CN, —C(O)NR⁹(CR¹⁹R²⁰)₁₋₁₂R¹¹,—C(O)N((R¹⁹R²⁰)₁₋₁₂R¹¹)₂, —NR⁹C(O)NR⁹(CR¹⁹R²⁰)₁₋₁₂CO₂R⁹, unsubstitutedor substituted tetrazolyl, or —CO₂R²¹. In another embodiment, R⁹ is H orC₁-C₆ alkyl; and R¹⁰ is H, aryl, alkyl, heteroaryl, heteroaralkyl,aralkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl, wherein eachmember of R¹⁰ except H is optionally substituted with 1-2 R¹² moieties.In another embodiment, R¹² is halo, —CN, —CF₃, —OR¹³, —C(O)OR¹³,—NR¹³R¹⁴, —NO₂, C₁-C₆ alkyl, phenyl, or benzyl; R¹³ is H or C₁-C₆ alkyl;and R¹⁴ is H or C₁-C₆ alkyl.

In another embodiment, R⁹ is H; and R¹⁰ is C₁-C₆ alkyl, phenyl,naphthyl, thienyl, benzyl, benzothienyl, pyrazolyl, quinolinyl,tetrazolyl, thienylmethyl, pyridylmethyl, naphthylmethyl, phenethyl,cyclohexyl, cyclopentyl, cyclopropyl, indanyl, cyclohexylmethyl,cyclopropylmethyl, piperidinyl, wherein each member of R¹⁰ is optionallysubstituted with 1-2 moieties independently selected from the groupconsisting of phenyl, benzyl, methyl, F, Cl, Br, I, —CN, —CF₃, —OH,—OCH₃, —CO₂H, —CO₂CH₃, —NH₂, —NHCH₃, —N(CH₃)₂, and —NO₂.

In another embodiment, R¹ is —CO₂H, tetrazolyl, —C(O)NHCN, —C(O)NHR³⁰,—C(O)NH-tetrazolyl, —C(O)NH-(1-naphthyl)ethyl, or —NHSO₂R³⁰; and R³⁰ isphenyl optionally substituted with 1-2 moieties selected from the groupconsisting of —OCH₃, F, Cl, Br, I, OH, and CO₂H.

In another embodiment, the present invention provides compounds offormula II:

In another embodiment, the present invention provides compounds offormula II, wherein R³² is H, halo, CF₃, or methyl.

In another embodiment, the present invention provides compounds offormula II, wherein R³¹ is t-butyl; phenyl; cyclopentyl; cyclohexyl;cyclobutyl; cyclopropyl; thienyl; phenyl substituted with —NH₂; orN-pyrazolyl optionally substituted with 1-2 methyl groups.

In another embodiment, the present invention provides compounds offormula II-a:

In another embodiment, the present invention provides compounds offormula III:

In another embodiment, the present invention provides compounds offormula III-a:

In another embodiment, the present invention provides compounds offormula III-b:

In another embodiment, the present invention provides compounds offormula IV:

In another embodiment, the present invention provides compounds offormula IV, wherein R³⁴ is H, halo, CF₃, or methyl.

In another embodiment, the present invention provides compounds offormula IV, wherein R³³ is phenyl, cyclopentyl, cyclobutyl, cyclopropyl,or allyl.

In another embodiment, the present invention provides compounds offormula IV-a:

Representative compounds of the present invention are shown in Table 1below.

TABLE 1 Cpd. No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

Preferred compounds include compounds 1-18.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)₂, carboxy and —C(O)O-alkyl. Non-limiting examples of suitablealkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl, aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl- group in which the aryland alkyl are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyland the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁and Y₂ can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietyare methylene dioxy, ethylenedioxy, —C(CH₃)₂— and the like which formmoieties such as, for example:

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” mayalso mean a single moiety (e.g., carbonyl) which simultaneously replacestwo available hydrogens on the same carbon atom on a ring system.Example of such moiety is pyrrolidone:

“Heterocyclylalkyl” means a heterocyclyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable heterocyclenyl groupsinclude 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl,1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazole, dihydrooxazole,dihydrooxadiazole, dihydrothiazole, 3,4-dihydro-2H-pyran,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”may also mean a single moiety (e.g., carbonyl) which simultaneouslyreplaces two available hydrogens on the same carbon atom on a ringsystem. Example of such moiety is pyrrolidinone:

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process or natural source or combinationthereof. Thus, the term “purified”, “in purified form” or “in isolatedand purified form” for a compound refers to the physical state of saidcompound after being obtained from a purification process or processesdescribed herein or well known to the skilled artisan, in sufficientpurity to be characterizable by standard analytical techniques describedherein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS Pharm Sci Tech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

Compounds of Formula I, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (I) as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.)Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula (I) cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates, esters and prodrugs of the compounds of Formula I, areintended to be included in the present invention.

In such esters, unless otherwise specified, any alkyl moiety presentpreferably contains from 1 to 18 carbon atoms, particularly from 1 to 6carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkylmoiety present in such esters preferably contains from 3 to 6 carbonatoms. Any aryl moiety present in such esters preferably comprises aphenyl group.

Generally, the compounds of formula I can be prepared by a variety ofmethods well known to those skilled in the art, for example, by themethods as outlined in the examples disclosed herein.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of formula I are useful as HCVRNA-dependent RNA polymerase inhibitors. Accordingly, the presentcompounds are useful in the treatment or prevention ofdiseases/conditions that are treatable or preventable by inhibiting HCVRNA-dependent RNA polymerase. The present compounds are thus useful fortreating diseases/conditions such as HCV infection, HIV infection, AIDS(Acquired Immune Deficiency Syndrome), and related disorders. Thecompounds of formula I may also be used for the manufacture of amedicament to treat disorders associated with the HCV RNA-dependent RNApolymerase.

As used herein, the phrases “HCV RNA-dependent RNA polymeraseinhibitor”, “HCV RdRp inhibitor”, “inhibitor of HCV RNA-dependent RNApolymerase”, and “inhibitor of HCV RdRp” refer to compounds that arecapable of interacting with HCV RNA-dependent RNA polymerase andinhibiting its enzymatic activity. Inhibiting HCV RNA-dependent RNApolymerase enzymatic activity means reducing the ability of HCV RdRp toincorporate ribonucleotides into a growing HCV RNA strand. In somepreferred embodiments, such reduction of HCV RdRp activity is at least50%, more preferably at least 75%, and still more preferably at least90%. In other preferred embodiments, HCV RdRp activity is reduced by atleast 95% and more preferably by at least 99%. Preferred compounds arethose which have a IC₅₀ value less than 100 nM (more preferably lessthan 50 nM; most preferably less than 20 nM).

Preferably, such inhibition is specific, i.e., the HCV RdRp inhibitorreduces the ability of HCV RdRp to incorporate ribonucleotides into agrowing HCV RNA strand at a concentration that is lower than theconcentration of the inhibitor that is required to produce another,unrelated biological effect. Preferably, the concentration of theinhibitor required for HCV RdRp inhibitory activity is at least 2-foldlower, more preferably at least 5-fold lower, even more preferably atleast 10-fold lower, and most preferably at least 20-fold lower than theconcentration required to produce an unrelated biological effect.

In another aspect, this invention relates to methods of inhibiting HCVreplication in a cell. The methods comprise contacting a cell that isinfected by HCV with at least one compound of formula I or apharmaceutically acceptable salt, solvate or ester thereof or acomposition according to the invention. In some embodiments, the cell isa hepatocyte. However, HCV is capable of replication in cell types otherthan hepatocytes, and the methods of the invention are also effective insuch other cell types.

In some embodiments, the cell is a cultured cell that is capable ofsupporting replication of HCV. Cell culture systems that support HCVreplication can be prepared by infection of primary cell cultures orcell lines, or by cultivation of primary cells from a chronicallyinfected patient. Examples of such HCV replication systems can be founddescribed, e.g., in Lohmann et al., Science 285: 110-113 (1999), Blightet al., Science 290: 1972 (2000), and Barenschlager and Lohmann, J. Gen.Virology 81: 8631-1648 (2000). In other embodiments, the cell is locatedin a human or animal.

In a further aspect, the present invention provides a use of at leastone compound of formula I or a pharmaceutically acceptable salt, solvateor ester thereof for preparation of a medicament for use in prophylaxisor treatment of HCV infection.

In a further aspect, the invention provides methods for treating orpreventing a disease or condition associated with HCV infection,comprising administering to a mammal infected with HCV a therapeuticallyor prophylactically effective amount of at least one compound orcomposition according to the invention. The phrase “disease or conditionassociated with HCV infection” refers to any illness or condition causeddirectly or indirectly by infection with HCV. Preferably, the mammal isa human.

HCV is characterized by pronounced genomic variability, and HCVreplication leads to the rapid generation of virus variants. Holland etal., Current Topics in Microbiology and Immunology 176: 1-20 (1992)teaches that HCV exists, even within an individual patient, as a swarmof microvariants, a phenomenon the authors refer to as quasispecies.Therefore, the terms “hepatitis C virus” and “HCV”, as used herein, areintended to refer to any of such virus variants, or mixtures thereof.

The phrase “effective amount” or “therapeutically effective amount”, asused herein, refers to an amount sufficient to cause a benefit to amammal or sufficient to cause any beneficial change in any symptom ormarker associated with HCV infection. The phrase “marker associated withHCV infection” refers to any biological measure that correlates with HCVinfection and/or is predictive of clinical prognosis. Such markersinclude, without limitation, active virus and viral antigens.

The term “prophylactically effective amount”, as used herein, refers toan amount sufficient to prevent or reduce the severity of HCV symptomsin a mammal exposed to or infected by HCV. In some embodiments,prophylactic treatment includes administering a compound or compositionaccording to the invention to a patient found to carry HCV, but whichdoes not exhibit symptoms of hepatitis C disease. Prophylactic treatmentalso includes administering a compound or composition according to theinvention to a patient who shows an improved disease state, but whichstill carries HCV and is at risk of recurrence of symptomatic disease.

The effective (e.g., therapeutically or prophylactically) amount of theHCV RdRp inhibitor administered will be determined empirically, and willbe based on such considerations as the particular inhibitor used, theage, body weight, and condition of the individual, the treatment effectdesired, administration route, and the like. A typical dose ranges fromabout 0.1 mg/kg to about 1,000 mg/kg per dose, which can be given one toseveral times per day. A preferred dosage is about 1 to 250 mg/kg perdose.

Generally, the human oral dosage form containing the active ingredientscan be administered 1 or 2 times per day. The amount and frequency ofthe administration will be regulated according to the judgment of theattending clinician. A generally recommended daily dosage regimen fororal administration may range from about 1.0 milligram to about 1,000milligrams per day, in single or divided doses.

For administration of pharmaceutically acceptable salts of the abovecompounds, the weights indicated above refer to the weight of the acidequivalent or the base equivalent of the therapeutic compound derivedfrom the salt.

In yet another embodiment, the compounds of the invention may be used incombination (administered at the same time or sequentially) with one ormore additional agents for treating viral infections, e.g., antiviralagents or immunomodulatory agents. In some embodiments, the additionalagent is an inhibitor of HCV RdRp, HCV helicase, HCV protease, oranother HCV target protein.

Examples of such antiviral and/or immunomodulatory agents includeRibavirin (from Schering-Plough Corporation, Madison, N.J.) andLevovirin™ (from ICN Pharmaceuticals, Costa Mesa, Calif.), VP 50406™(from Viropharma, Incorporated, Exton, Pa.), ISIS 14803™ (from ISISPharmaceuticals, Carlsbad, Calif.), Heptazyme™ (from RibozymePharmaceuticals, Boulder, Colo.), VX 497™ (from Vertex Pharmaceuticals,Cambridge, Mass.), Thymosin™ (from SciClone Pharmaceuticals, San Mateo,Calif.), Maxamine™ (Maxim Pharmaceuticals, San Diego, Calif.),mycophenolate mofetil (from Hoffman-LaRoche, Nutley, N.J.), interferon(such as, for example, interferon-alpha, PEG-interferon alphaconjugates) and the like. “PEG-interferon alpha conjugates” areinterferon alpha molecules covalently attached to a PEG molecule.Illustrative PEG-interferon alpha conjugates include interferon alpha-2a(Roferon™, from Hoffman La-Roche, Nutley, N.J.) in the form of pegylatedinterferon alpha-2a (e.g., as sold under the trade name Pegasys™),interferon alpha-2b (Intron™, from Schering-Plough Corporation) in theform of pegylated interferon alpha-2b (e.g., as sold under the tradename PEG-Intron™), interferon alpha-2c (Berofor Alpha™, from BoehringerIngelheim, Ingelheim, Germany) or consensus interferon as defined bydetermination of a consensus sequence of naturally occurring interferonalphas (Infergen™, from Amgen, Thousand Oaks, Calif.).

As described above, this invention thus includes combinations comprisingan amount of at least one compound of formula I or a pharmaceuticallyacceptable salt, solvate or ester thereof, and an amount of one or moreadditional therapeutic agents listed above (administered together orsequentially) wherein the amounts of the compounds/treatments result indesired therapeutic effect.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like. Theamounts of the various actives in such combination therapy may bedifferent amounts (different dosage amounts) or same amounts (samedosage amounts). Thus, for illustration purposes, a compound of FormulaI and an additional therapeutic agent may be present in fixed amounts(dosage amounts) in a single dosage unit (e.g., a capsule, a tablet andthe like). A commercial example of such single dosage unit containingfixed amounts of two different active compounds is VYTORIN® (availablefrom Merck Schering-Plough Pharmaceuticals, Kenilworth, N.J.).

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange. Compounds of formula I may also be administered sequentially withknown therapeutic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of formula I may be administered either priorto or after administration of the known therapeutic agent. Suchtechniques are within the skills of persons skilled in the art as wellas attending physicians.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The inhibitory activityof the present compounds against HCV RNA-dependent RNA polymerase may beassayed by methods known in the art, for example, by using the methodsas described in the examples.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition. Thecompositions of the present invention comprise at least one activeingredient, as defined above, together with one or more acceptablecarriers, adjuvants or vehicles thereof and optionally other therapeuticagents (e.g., antiviral or immunomodulatory agents). Each carrier,adjuvant or vehicle must be acceptable in the sense of being compatiblewith the other ingredients of the composition and not injurious to themammal in need of treatment.

Accordingly, this invention also relates to pharmaceutical compositionscomprising at least one compound of formula I, or a pharmaceuticallyacceptable salt, solvate or ester thereof and at least onepharmaceutically acceptable carrier, adjuvant or vehicle. Thecompositions according to the invention may contain, in addition to theHCV RdRp inhibitor, diluents, fillers, salts buffers, stabilizers,solubilizers, and other materials well known in the art, provided thatsuch materials do not interfere with the effectiveness of the biologicalactivity of the active ingredient(s).

The present invention also discloses methods for preparingpharmaceutical compositions comprising at least one compound of thepresent invention as an active ingredient. In the pharmaceuticalcompositions and methods of the present invention, the activeingredients will typically be administered in admixture with carrier,adjuvant or vehicle materials suitably selected with respect to theintended form of administration, i.e. oral tablets, capsules (eithersolid-filled, semi-solid filled or liquid filled), powders forconstitution, oral gels, elixirs, dispersible granules, syrups,suspensions, and the like. For example, for oral administration in theform of tablets or capsules, the active drug component may be combinedwith any oral non-toxic pharmaceutically acceptable inert carrier, suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms)and the like. Moreover, when desired or needed, suitable binders,lubricants, disintegrating agents and coloring agents may also beincorporated in the mixture. Sweetening and flavoring agents andpreservatives may also be included where appropriate. Powers and tabletsmay comprise from about 5 to about 95 percent active ingredient.

Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethyl-cellulose, polyethylene glycol and waxes. Suitablelubricants include stearic acid, boric acid, sodium benzoate, sodiumacetate, sodium chloride, and the like. Disintegrants include starch,methylcellulose, guar gum and the like.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. HCV inhibitory activity and thelike. Suitable dosage forms for sustained release include layeredtablets containing layers of varying disintegration rates or controlledrelease polymeric matrices impregnated with the active components andshaped in tablet form or capsules containing such impregnated orencapsulated porous polymeric matrices.

Liquid form preparations include solutions, suspensions and emulsions.Water or water-propylene glycol solutions are useful for parenteralinjections. Sweeteners and pacifiers may be added for oral solutions,suspensions and emulsions. Liquid form preparations may also includesolutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions may take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose. Other examples of pharmaceutically acceptable formulations maybe found in Remington: The Science and Practice of Pharmacy, 20th Ed.,ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.

Compounds of the invention may be formulated and administered by anyroute known in art, including but not limited to, subcutaneous,parenteral, oral, sublingual, transdermal, topical, or intrarectal. Insome embodiments, oral administration is preferred. In otherembodiments, subcutaneous administration is preferred.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of formula I or apharmaceutically acceptable salt, solvate or ester thereof and at leastone pharmaceutically acceptable carrier, adjuvant or vehicle.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of formula I or a pharmaceutically acceptable salt,solvate or ester thereof and an amount of at least one additionaltherapeutic agent listed above, wherein the amounts of the two or moreingredients result in desired therapeutic effect.

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

EXAMPLES

In general, the compounds of this invention may be prepared from knownor readily prepared starting materials, following methods known to oneskilled in the art and those illustrated below. All stereoisomers andtautomeric forms of the compounds are contemplated.

Preparative Example 1

An analogous procedure can be found in J. Am. Chem. Soc. 1954, 5579.

To dry acetone (85 mL) was added 2-acetamidophenol (10 g, 66 mmol),potassium carbonate (9.5 g, 69 mmol) and benzyl bromide (12.2 g, 71mmol). The reaction was heated to reflux for 16 h, then cooled to roomtemperature. The acetone was removed under vacuum, resulting in anorange colored solid. Trituration/sonication of this solid with 1:1ether:hexanes produced a pure product (i, 12.8 g, 80%) as a beige solid.¹H-NMR (300 MHz, CDCl₃) δ 8.22 (d, J=7.0 Hz, 1 H), 7.6 (br, 1 H),7.27-7.1 (m, 5H), 6.88-6.78 (m, 3 H), 5.15 (s, 2 H), 2.00 (s, 3H).

To the benzylated amino phenol i (6.0 g, 25 mmol) in ethanol (25 mL) wasadded 6 N aqueous KOH (20 mL) and the mixture was refluxed and stirredovernight. The reaction was cooled to room temperature (note 1), ether(250 mL) added, and the layers separated. The organic layer was driedover sodium sulfate and concentrated to give a light brown oil whichslowly solidified into a tan solid (2-benzyloxy-phenylamine, 4.5 g,90%). ¹H-NMR (300 MHz, CDCl₃) δ 7.46-7.32 (m, 5 H), 6.87 (d, J=7.9 Hz, 1H), 6.84 (d, J=6.9 Hz, 1H), 6.80-6.69 (m, 2 H), 5.10 (s, 2 H), 3.83 (br,2 H). HRMS (positive mode electrospray) calcd for C13H14NO [M+H]⁺200.108, found 200.097.

Example 1

A solution of 6.25 g (29.5 mmol) of diethyl 3,5-pyrazoledicarboxylate(1) in 225 mL of acetone was added 11.7 g (36 mmol) of cesium carbonate,followed after 10 min by the addition of 5.3 mL (36 mmol) of t-butylbromoacetate and the mixture was stirred overnight at room temperature.Since TLC analysis confirmed that the reaction was complete (R_(f)product=0.6 (7:3 hexanes:ethyl acetate)), the mixture was filtered andconcentrated to give quantitatively1-tert-butoxycarbonylmethyl-1H-pyrazole-3,5-dicarboxylic acid diethylester (2) as a clear oil as indicated by ¹H NMR (containing a trace oft-butyl bromoacetate). (δ(300 MHz, CDCl₃) 7.14 (s, 1H), 5.15 (s, 2H),4.29 (q, J=7.1 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H), 1.30 (s, 9 H), 1.27 (t,J=7.1 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H)). This material was used withoutfurther purification in the next reaction.

According to a related procedure (Lee, H. H.; Cain, B. F.; Denny, W. A.;Buckleton, J. S.; Clark, G. R. J. Org. Chem. 1989, 54, 428-431) asolution of 9.6 g (29.4 mmol) of pyrazole triester (2) in 250 mL oftetrahydrofuran and 50 mL of water was cooled to −10° C. and 30 mL (30mmol) of a chilled 1M LiOH solution was added dropwise. The reactionmixture was slowly allowed to warm to 0° C., then was stirred at 0° C.for an additional hour. The mixture was then diluted with 600 mL ofethyl acetate and acidified to pH=1 with 1 N HCl solution. The organicextract was washed with brine, dried over sodium sulfate, and evaporatedto a residue which was chromatographed on silica gel (1% methanol indichloromethane, followed by 90:9:1 dichloromethane:methanol:aceticacid) to give 4.66 g (53%) of desired1-tert-butoxycarbonylmethyl-1H-pyrazole-3,5-dicarboxylic acid 3-ethylester L3), as well as 2.3 g of recovered starting triester (2). ¹H NMRof 3 (300 MHz, CDCl₃) δ 7.49 (s, 1H), 5.28 (s, 2H), 4.42 (q, J=7.1 Hz),1.45 (s, 9 H), 1.40 (t, J=7.2 Hz, 3H).

A sample of 3.3 g (7.71 mmol) of monoacid pyrazole 3 was treated with 25mL of 98:2 trifluoroacetic acid (TFA):water solution and the reactionmixture was stirred at room temperature for 3 h. The mixture was thenconcentrated, taken up in acetonitrile, and concentrated again to give1.4 g (75% yield) of 1-carboxymethyl-1H-pyrazole-3,5-dicarboxylic acid3-ethyl ester (4) as a white solid, which was used without any furtherpurification in the next step. ¹H NMR of 4 (300 MHz, DMSO) δ 7.23 (s,1H), 5.31 (s, 2 H), 4.29 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H). MScalcd for C₉H₉N₂O₆ [M−H], 241.046 found 241.158.

A solution of 1.10 g (4.54 mmol) of diacid 4 in 15 mL of DMF was added2.04 g (10.1 mmol) of (1S,2S)-(+)-2-benzyloxycyclohexylamine and 4.0 mL(23 mmol) of diisopropylethylamine (DIEA). After stirring for 5 min 3.84g (10.1 mmol) of HATU was added and the reaction mixture was stirred atroom temperature for 1 h. The mixture was then diluted with 600 mL ofethyl acetate, rinsed with 0.1 N NaOH solution, water (three times), 0.1N HCl solution, and brine. The organic extract was then dried oversodium sulfate and concentrated to give a yellowish solid, which waschromatographed on silica gel (3% methanol in dichloromethane) to afford1.33 g (47%) of5-(2-benzyloxy-cyclohexylcarbamoyl)-1-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-1H-pyrazole-3-carboxylicacid ethyl ester (6) as a white solid. MS calcd for C₃₅H₄₅N₄O₆ [M+H]⁺617.334, found 617.448. ¹H NMR spectra (in multiple solvents) for thediamide reflected an equilibrium of several conformers which causedbroadening and peak splitting.

A solution of 1.08 g (1.75 mmol) of pyrazole ester 5 (compound 48 offormula I) in 60 mL of tetrahydrofuran and 15 mL of water was added 6.0mL (6 mmol) of 1 M LiOH solution and the reaction mixture was stirredovernight at rt. The mixture was then concentrated, diluted with water,and acidified at 0° C. to pH=2 with 1 N HCl solution, when a whiteprecipitate formed. The white solid was filtered off, washed with water,and dried to afford 0.7 g (70%) of crude product (90% pure), which waschromatographed on silica gel (90:9:1 dichloromethane:methanol:aceticacid) to afford 0.377 g (37% yield) of5-(2-Benzyloxy-cyclohexylcarbamoyl)-1-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-1H-pyrazole-3-carboxylicacid as a white solid as indicated by ¹H NMR. MS calcd for C33H39N4O6[M−H]⁻ 587.287, found 587.466. ¹H NMR (300 MHz, DMSO) δ 8.47 (d, J=8.5Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.37 (s, 1H), 7.34-7.14 (m, 10H), 5.37(d, J=16 Hz, 2H), 5.18 (d, J=16 Hz, 1H), 4.59-4.45 (m, 4H), 3.77 (m,1H), 3.64 (m, 1H), 3.40 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H), 1.8-1.6 (m,5H), 1.35-1.17 (m, 9H).

Example 2

A solution of 227 mg (0.386 mmol) of5-(2-benzyloxy-cyclohexylcarbamoyl)-1-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-1H-pyrazole-3-carboxylicacid in 3 mL of dimethylformamide was cooled at 0° C. To the above coldsolution was added 0.606 mL (3.48 mmol) of N,N-diisopropylethylamine(DIEA), followed by 441 mg (1.16 mmol) of HATU, and 2.3 mL (1.16 mmol)of 0.5 M solution of ammonia in 1,4-dioxane. The resulting mixture wasallowed to warm up to room temperature, and stirred at room temperatureovernight. Since analysis by LC-MS indicated that the desired productwas the major component, the reaction mixture was diluted with ethylacetate, washed with 1N citric acid solution, then with saturated sodiumbicarbonate solution, brine, dried over sodium sulfate and evaporated togive a residue. This residue was chromatographed on silica gel (5%methanol in dichloromethane) to give 88 mg (38% yield) of1-[(2-Benzyloxy-cyclohexylcarbamoyl)-methyl]-1H-pyrazole-3,5-dicarboxylicacid 3-amide 5-[(2-benzyloxy-cyclohexyl)-amide] as a beige solid asindicated by ¹H NMR; LC-MS—calcd for C₃₃H₄₁N₅O₅ [M+H]⁺ 588.31, found588.3.

To an ice cold solution of 85 mg (0.145 mmol) of1-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-1H-pyrazole-3,5-dicarboxylicacid 3-amide 5-[(2-benzyloxy-cyclohexyl)-amide] in 1.5 mL of pyridinewas added 0.02 mL (0.22 mmol) of phosphorus oxychloride, and theresulting mixture was stirred at 0° C. for 2 h. The mixture was thendiluted with ethyl acetate, washed with 1 N HCl solution, dried oversodium sulfate and concentrated to give 95 mg of a green solid which waschromatographed on silica gel (5% methanol in dichloromethane) to afford40 mg (48% yield) of2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-5-cyano-2H-pyrazole-3-carboxylicacid (2-benzyloxy-cyclohexyl)-amide (compound 187) as an off-white solidas indicated by ¹H NMR; LC-MS—calcd for C₃₃H₃₉N₅O₄ [M+H]⁺ 570.3, found570.2.

According to a modification of a literature procedure (Herr, R. J.Bioorg. Med. Chem. 2002, 10, 3379-3393) to a solution of 39 mg (0.068mmol) of2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-5-cyano-2H-pyrazole-3-carboxylicacid (2-benzyloxy-cyclohexyl)-amide in 1 mL of toluene and 1 mL ofdimethylformamide was added 56 mg (0.41 mmol) of triethylaminehydrochloride, and 26 mg (0.41 mmol) of sodium azide and the resultingheterogeneous mixture was heated at 120° C. overnight. Since analysis byLC-MS indicated that the desired product was present only as 70% of themixture, 56 mg (0.41 mmol) of triethylamine hydrochloride, and 26 mg(0.41 mmol) of sodium azide was added, and the resulting reactionmixture was heated at 120° C. overnight. The mixture was then cooled toroom temperature, diluted with water and ethyl acetate, acidified with 2mL of concentrated HCl solution, and extracted with ethyl acetate. Thecombined organic extracts were washed with water, brine, dried oversodium sulfate, filtered and concentrated to give 35 mg of a beige solidwhich was purified via reverse-phase chromatography to afford (afterlyophilization) 19 mg (46% yield) of2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-5-(1H-tetrazol-5-yl)-2H-pyrazole-3-carboxylicacid (2-benzyloxy-cyclohexyl)-amide (compound 18) as a white solid asindicated by ¹H-NMR; LC-MS calcd for C₃₃H₄₀N₈O₄ [M+H]⁺ 613.32; found613.3.

A general scheme and experimental procedures to prepare the compounds offormulas 11, 13, 17, 19, 26, 30-33, 35-38, 41, 42, 44, 45, 47, 55, 58,60, 61, 67, 71, 75, 78-80, 82, 84, 85, 87, 90, 91, 96, 97, 102, 106,108, 112, 113, 118, 121, 124, 135, 144, 167, 172, 183, 196 and 205 inTable 1 are shown below.

5-Nitro-2H-pyrazole-3-carboxylic acid methyl ester

A solution of 5-Nitro-2H-pyrazole-3-carboxylic acid (5 gm, 32 mmol) in100 ml of 2% sulfuric acid methanol was refluxed for 20 hours. Themixture was cooled to room temperature and added to saturated sodiumbicarbonate. The mixture was extracted with ethyl acetate three times toobtain 3.59 gm of title product after drying over magnesium sulfate,filtering and evaporating to dryness. ESI M+1=171.

2-tert-Butoxycarbonylmethyl-5-nitro-2H-pyrazole-3-carboxylic acid methylester

To a stirring mixture of 5-nitro-2H-pyrazole-3-carboxylic acid methylester (3.5 gm, 20.5 mmol) dissolved in 150 ml of acetone was addedcesium carbonate (8.01 gm, 24.6 mmol) followed by the addition oftert-butyl bromoacetate (3.61 ml). After 5 hours the solids werefiltered and the mixture chromatographed on silica gel using 10% ethylacetate/hexanes as the eluent to obtain 4.16 gm of pure title product.ESI M+1=286.

5-Amino-2-tert-butoxycarbonylmethyl-2H-pyrazole-3-carboxylic acid methylester

A solution of2-tert-Butoxycarbonylmethyl-5-nitro-2H-pyrazole-3-carboxylic acid methylester (3 gm) in ethyl acetate (60 ml) and acetic acid (4.5 ml) washydrogenated at 50 psi hydrogen in the presence of 1.5 gm of 10%palladium/carbon for 3 hours. The mixture was then filtered andevaporated to obtain 2.62 gm of pure title product. ESI M+1=256.

5-tert-Butoxycarbonylamino-2-tert-butoxycarbonylmethyl-2H-pyrazole-3-carboxylicacid methyl ester

To a solution of5-Amino-2-tert-butoxycarbonylmethyl-2H-pyrazole-3-carboxylic acid methylester (1 gm, 3.92 mmol) in 20 ml of dichloromethane was addedtriethylamine (0.6 ml) followed by di-tert.butyldicarbonate (1 gm).After stirring for 5 hours the mixture was washed with 1N hydrochloricacid, dried over magnesium sulfate, filtered and evaporated to obtain0.53 gm of title product. ESI M+1=356.

5-tert-Butoxycarbonylamino-2-carboxymethyl-2H-pyrazole-3-carboxylic acid

To a solution of5-tert-Butoxycarbonylamino-2-tert-butoxycarbonylmethyl-2H-pyrazole-3-carboxylicacid methyl ester (0.5 gm) dissolved in 25 ml of tetrahydrofuran wasadded 5 ml of 1M lithium hydroxide. After stirring the reaction mixtureat 60 C for 2 hours, 1N hydrochloric acid was added and the productextracted with dichloromethane. The extract was dried over magnesiumsulfate, filtered and evaporated to obtain 0.49 gm of title product. ESIM+1=286.

{5-(2-Benzyloxy-cyclohexylcarbamoyl)-1-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-1H-pyrazol-3-yl}-carbamicacid tert-butyl ester

To a solution of5-tert-Butoxycarbonylamino-2-carboxymethyl-2H-pyrazole-3-carboxylic acid(0.45 gm, 1.57 mmol) in 15 ml of N,N-dimethylformamide was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.89 gm,4.71 mmol), hydroxybenztriazole (0.63 gm, 4.71 mmol) andN-methylmorpholine (1 ml, 9.4 mmol). The reaction mixture was stirredfor 4 hours after which the mixture was added to brine and extractedwith ethyl acetate. The ethyl acetate layer containing the product waswashed with saturated bicarbonate solution and then dried over magnesiumsulfate, filtered and evaporated to obtain 0.68 gm of pure product afterchromatography on silica gel using 50% ethyl acetate/hexanes as theeluent. ESI M+1=660.

5-Amino-2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylicacid (2-benzyloxy-cyclohexyl)-amide

To a solution of{5-(2-Benzyloxy-cyclohexylcarbamoyl)-1-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-1H-pyrazol-3-yl}-carbamicacid tert-butyl ester (0.5 gm) in 5 ml of dichloromethane was added 1 mlof 4N hydrochloric acid/dioxane. After stirring for 6 hours the mixturewas evaporated to dryness to obtain 0.41 gm of title product as thehydrochloride salt. ESI M+1=560.

5-Benzenesulfonylamino-2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylicacid (2-benzyloxy-cyclohexyl)-amide

5-Amino-2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylicacid (2-benzyloxy-cyclohexyl)-amide (40 mg, 0.067 mmol) was dissolved in1 ml of dry pyridine. Benzenesulfonyl chloride (0.0085 ml) was added andthe reaction mixture stirred for 1 hour. The mixture was added to brineand extracted with dichloromethane. The dichloromethane extract wasdried over magnesium sulfate, filtered. 29 mg of title compound wasobtained after preparative thin layer chromatography using 50% ethylacetate/hexanes as the eluent. ESI M+1=700.

5-Benzoylamino-2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylicacid (2-benzyloxy-cyclohexyl)-amide

5-Amino-2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylicacid (2-benzyloxy-cyclohexyl)-amide (0.05 gm, 0.008 mmol) was dissolvedin 1 ml of dichloromethane and 0.033 ml of triethylamine. Benzoylchloride (0.014 ml) was added and the reaction mixture stirred for 2hours. ESI M+1=664.

In a similar manner, the 3-urea derivatives were prepared by treatingthe compound with a suitable alkyl or aryl isocyanate.

Assay for HCV RNA-dependent RNA Polymerase Activity

Inhibitory activity of the present compounds against HCV RNA-dependentRNA polymerase was assayed according to the methods disclosed in UnitedStates Patent Application US2004/038993, content of which isincorporated herein by reference; and those described in Ferrari, E.;Wright-Minogue, J.; Fang, J. W. S.; Baroudy, B. M.; Lau, J. Y. N.; Hong,Z. J. Virol. 1999, 73, 1649.

Briefly, 50 μl reactions containing 20 mM HEPES (pH 7.3), 7.5 mM DTT, 20units/ml RNasIN, 0.5 μg/ml biotinylated oligoG₁₂, 5 μg/ml polyC, 5 μMGTP, 20 μCi/ml [³H]-GTP, 10 mM MgCl₂, 60 mM NaCl, 100 μg/ml BSA, and 50nM NS5B (Δ21) were incubated at room temperature for three hours in96-well plates with or without test compounds. Assay was terminated bythe addition of 50 μl 10 mg/ml streptavidin-coated SPA beadssupplemented with 100 mM EDTA, and the incorporation of labeled GTPdetermined by a TopCount Scintillation Counter. IC₅₀ values werecalculated from single experiments using 11 serial 2-fold dilutions(0.05-50 μM), and data were considered reliable only when the IC₅₀ valueof a positive internal control was within standard deviation range.

HCV RNA-dependent RNA polymerase inhibitory activities forrepresentative compounds are shown in Table 2 below. IC₅₀ values greaterthan 1 μM are designated as D class. IC₅₀ values between 0.1 and 1 μMare designated as B class. IC₅₀ values between 0.05 and 0.1 μM aredesignated as B class. IC₅₀ values less than 0.05 μM are designated as Aclass.

TABLE 2 Cpd. Δ21 Activity Cpd. Δ21 Activity No. (IC₅₀ μM) No. (IC₅₀ μM)1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 A 12 A 13 A 14 A 15 A 16 A17 A 18 B 19 B 20 B 21 B 22 B 23 B 24 B 25 B 26 B 27 B 28 B 29 B 30 B 31B 32 B 33 B 34 B 35 B 36 B 37 B 38 B 39 B 40 B 41 B 42 B 43 B 44 B 45 B46 B 47 B 48 B 49 C 50 C 51 C 52 C 53 C 54 C 55 C 56 C 57 C 58 C 59 C 60C 61 C 62 C 63 C 64 C 65 C 66 C 67 C 68 C 69 C 70 C 71 C 72 C 73 C 74 C75 C 76 C 77 C 78 C 79 C 80 C 81 C 82 C 83 C 84 C 85 C 86 C 87 C 88 C 89C 90 C 91 C 92 C 93 C 94 C 95 C 96 C 97 C 98 C 99 C 100 C 101 C 102 C103 C 104 C 105 C 106 C 107 C 108 C 109 C 110 C 111 C 112 C 113 C 114 C115 C 116 C 117 C 118 C 119 C 120 C 121 C 122 C 123 C 124 C 125 C 126 C127 C 128 C 129 C 130 C 131 C 132 C 133 C 134 C 135 C 136 C 137 C 138 C139 C 140 C 141 C 142 C 143 C 144 C 145 C 146 C 147 C 148 C 149 C 150 C151 C 152 C 153 C 154 C 155 C 156 C 157 C 158 C 159 C 160 C 161 C 162 C163 D 164 C 165 C 166 C 167 C 168 D 169 D 170 D 171 D 172 D 173 D 174 D175 D 176 D 177 D 178 D 179 D 180 D 181 D 182 D 183 D 184 D 185 D 186 D187 D 188 D 189 D 190 D 191 D 192 D 193 D 194 D 195 D 196 D 197 D 198 D199 D 200 D 201 D 202 D 203 D 204 D 205 D 206 D 207 D 208 D 209 D 210 D211 D

The IC₅₀ values for a representative, non-limiting, group of compoundsof the invention are shown in Table 3:

TABLE 3 Compound Δ21 Activity (IC₅₀ μM)

0.02

0.023

0.02

0.037

0.033

0.024

0.15

0.032

0.055

0.035

0.036

0.037

0.041

0.041

0.042

0.045

0.074

0.05

While the present invention has been described with in conjunction withthe specific embodiments set forth above, many alternatives,modifications and other variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

1. A compound of formula I:

or a pharmaceutically acceptable salt, solvate or ester thereof,wherein: X is C(R⁸); R⁸ is H, CF₃, C₁-C₆ alkyl, halo(C₁-C₆)alkyl; Y isC(O); R¹ is —CO₂R⁹, —C(O)NR⁹R¹⁰, —NR⁹SO₂R¹⁰, —C(O)NR⁹CN, unsubstitutedtetrazolyl; R² is phenyl or cyclohexyl, wherein each member of R² isoptionally substituted with 1-2 R¹² moieties; R³ is H or C₁-C₆ alkyl; R⁴is H, or C₁-C₆ alkyl; R⁵ is H, or C₁-C₆ alkyl; R⁶ is cyclohexylsubstituted with —OR¹³; R⁷ is H or C₁-C₆ alkyl; each R⁹ is independentlyH, or alkyl; each R¹⁰ is independently alkyl or phenyl, wherein each R¹⁰is optionally substituted with 1-2 R¹² moieties; each R¹² isindependently halo, alkyl, —CF₃, —OR¹³, naphthalene or —C(O)OR¹³; andeach R¹³ is independently H, alkyl, cycloalkylalkyl, benzyl oralkylthiophene.
 2. The compound of claim 1, wherein X is C(R⁸).
 3. Thecompound of claim 2, wherein R⁸ is H.
 4. The compound of claim 1,wherein R³ is H or CH₃ and R⁷ is H or CH₃.
 5. The compound of claim 1,wherein: each R¹² is independently —OR¹³, alkyl, halo, or CF₃; and R¹³is alkyl; cycloalkylalkyl; benzyl or alkylthiophene.
 6. The compound ofclaim 5, wherein R¹³ is benzyl; cyclopentylmethyl; cyclohexylmethyl;cyclobutylmethyl; cyclopropylmethyl; C₁-C₆ alkyl; or thienylmethyl. 7.The compound of claim 1, wherein R¹² is halo, —CF₃, —OR¹³, —C(O)OR¹³,C₁-C₆ alkyl, or naphthalene; and R¹³ is H or C₁-C₆ alkyl.
 8. Thecompound of claim 1, wherein: R⁹ is H; and R¹⁰ is C₁-C₆ alkyl, orphenyl, wherein each member of R¹⁰ is optionally substituted with 1-2R¹² moieties.
 9. The compound of claim 1, wherein R¹ is —CO₂H,tetrazolyl, —C(O)NHCN, —C(O)NHR³⁰, or —NHSO₂R³⁰; and R³⁰ is phenyloptionally substituted with 1-2 moieties selected from the groupconsisting of —OCH₃, F, Ci, Br, I, OH, and CO₂H.
 10. The compound ofclaim 1, represented by formula II:


11. The compound of claim 10, wherein R³² is H, halo, CF₃, or methyl.12. The compound of claim 10, wherein R³¹ is t-butyl; phenyl;cyclopentyl; cyclohexyl; cyclobutyl; cyclopropyl; or thienyl.
 13. Thecompound of any one of claims 10-12, represented by formula II-a:


14. The compound of claim 1, represented by formula III:


15. The compound of claim 14, represented by formula III-a:


16. The compound of claim 14, represented by formula III-b:


17. The compound of claim 1, represented by formula IV-a:


18. The compound of claim 1, selected from Table 1: TABLE 1 Cpd. No.Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211


19. The compound of claim 18, wherein the compound is selected fromcompounds with compound numbers 1-18.
 20. A pharmaceutical compositioncomprising at least one compound of claim 1, and at least onepharmaceutically acceptable carrier, adjuvant or vehicle.
 21. Thepharmaceutical composition of claim 20, further comprising one or moreadditional antiviral agent(s).
 22. The pharmaceutical composition ofclaim 21, further comprising an interferon or pegylated interferon. 23.The pharmaceutical composition of claim 22, wherein said additionalantiviral agent is ribavirin and said interferon is α-interferon orpegylated interferon.
 24. A method of inhibiting HCV replication in acell in need thereof, comprising contacting said cell with an effectiveamount of at least one compound of claim 1.